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Updated: Feb 9, 2026

Detection of Targetable Alterations in Non-small Cell Lung Cancer using Next-generation Sequencing
Published on: October 10, 2025
Targeted DNA sequencing of non-small cell lung cancer identifies mutations associated with brain metastases
George D Wilson1,2, Matthew D Johnson1,3, Samreen Ahmed2
1Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI, USA.
Introduction:
This study explores the hypothesis that dominant molecular oncogenes in non-small cell lung cancer (NSCLC) are associated with metastatic spread to the brain.
Methods:
NSCLC patient groups with no evidence of metastasis, with metastatic disease to a non-CNS site, who developed brain metastasis after diagnosis, and patients with simultaneous diagnosis of NSCLC and metastatic brain lesions were studied using targeted sequencing.
Results:
In patients with brain metastasis versus those without, only 2 variants (one each in BCL6 and NOTHC2) were identified that occurred in ≥ 4 NSCLC of patients with brain metastases but ≤ 1 of the NSCLC samples without brain metastases. At the gene level, 20 genes were found to have unique variants in more than 33% of the patients with brain metastases. When analyzed at the patient level, these 20 genes formed the basis of a predictive test to discriminate those with brain metastasis. Further analysis showed that PI3K/AKT signaling is altered in both the primary and metastases of NSCLC patients with brain lesions.
Conclusion:
While no single variant was associated with brain metastasis, this study describes a potential gene panel for the identification of patients at risk and implicates PI3K/AKT signaling as a therapeutic target.
Insights
This study investigated molecular oncogenes in non-small cell lung cancer (NSCLC) and brain metastasis. A gene panel may predict brain metastasis risk, and PI3K/AKT signaling is a potential therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Non-small cell lung cancer (NSCLC) poses a significant health challenge.
- Metastatic spread, particularly to the brain, is a critical factor in NSCLC patient outcomes.
- Identifying molecular drivers of brain metastasis is crucial for targeted therapies.
Purpose of the Study:
- To test the hypothesis that dominant molecular oncogenes in NSCLC are linked to brain metastatic spread.
- To identify potential molecular markers for predicting brain metastasis risk in NSCLC patients.
- To explore the role of specific signaling pathways in NSCLC brain metastasis.
Main Methods:
- Targeted sequencing was employed on NSCLC patient cohorts.
- Patient groups included those with no metastasis, non-CNS metastasis, and brain metastasis.
- Analysis focused on identifying genetic variants associated with brain metastatic disease.
Main Results:
- No single genetic variant was exclusively associated with brain metastasis.
- A panel of 20 genes showed unique variants in over 33% of patients with brain metastases.
- PI3K/AKT signaling pathway alterations were observed in both primary NSCLC and brain metastases.
Conclusions:
- A gene panel shows promise for identifying NSCLC patients at risk of brain metastasis.
- PI3K/AKT signaling is implicated in the development of NSCLC brain metastases.
- This research suggests potential therapeutic strategies targeting the PI3K/AKT pathway.
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